Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression
Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression
复制标题
Wnt5a 通过 IL-10 诱导肿瘤相关巨噬细胞的 M2 极化，促进结直肠癌进展。
DOI：
10.1186/s12964-020-00557-2
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发表时间：
2020-03-30
影响因子：
8.4
通讯作者：
Xiong, Bin
中科院分区：
文献类型：
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作者：
Liu, Qing;Yang, Chaogang;Xiong, Bin
肿瘤微环境中的肿瘤相关巨噬细胞（tumor associated macrophages, tam）影响肿瘤的发生、侵袭和转移。多项研究表明，Wnt5a主要在肿瘤间质中表达，尤其是在tam中。然而，Wnt5a是否调控结直肠癌（CRC）中tam的极化和生物学功能尚不完全清楚。方法采用免疫荧光染色法检测63例结直肠癌患者结直肠组织中CD68和Wnt5a的表达（对照20例正常组织）。采用RT-qPCR、流式细胞术、ELISA及抑制剂等方法探讨Wnt5a在tam极化中的作用。通过克隆形成和transwell实验检测wnt5a处理巨噬细胞对体外肿瘤增殖、迁移和侵袭的影响。最后，采用异种移植模型来证实Wnt5a(+) tam对CRC肿瘤发生的影响。结果我们发现高Wnt5a(+)CD68(+)/CD68(+) TAM比例与CRC患者预后不良显著相关，Wnt5a(+) TAM是一种m2样TAM亚型。随后，我们发现Wnt5a诱导巨噬细胞分泌IL-10， IL-10作为自分泌细胞因子诱导巨噬细胞M2极化。IL-10中和抗体完全逆转Wnt5a的pro-M2作用。在机制上，巨噬细胞中wnt5a介导的IL-10表达需要CaKMII-ERK1/2-STAT3通路。wnt5a诱导的M2巨噬细胞促进结直肠癌细胞的增殖、迁移和侵袭;TAMs中Wnt5a的敲低显著损害了TAMs的促肿瘤功能。结论Wnt5a可通过调节CaKMII-ERK1/2-STAT3通路介导的IL-10分泌，诱导tam的M2极化，最终促进结直肠癌的肿瘤生长和转移。
Background Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood. Methods Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a-treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a(+) TAMs on CRC tumorigenesis. Results We found that high Wnt5a(+)CD68(+)/CD68(+) TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a(+) TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5a-mediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs. Conclusions Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway-mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.